One in five Americans smoke tobacco. Each year over 440,000 people in the US and 5 million worldwide die from smoking-related illness, and the global mortality toll is rising. Pharmacotherapy for smoking cessation is highly cost effective, but relapse rates are high, and fewer than 20% who attempt cessation are successful on a given attempt. After completion of smoking cessation treatment, recently abstinent smokers face repeated environmental cues that often trigger relapse. Cue exposure therapies are directed at reducing cravings in response to such cues, but these strategies have had only limited efficacy to date. Now, a novel strategy for strengthening the efficacy of cue exposure approaches is at hand. Basic research has identified d-cycloserine (DCS), a partial agonist of the NMDA receptor, as an agent capable of enhancing extinction learning. Following success in animal models, DCS was first applied to the enhancement of extinction learning for the treatment of acrophobia. Ongoing study has further supported the efficacy of single-dose applications of DCS to enhance the efficacy of exposure based treatments across the anxiety disorders, presumably by enhancing the memory of successful exposure sessions. There is also encouraging evidence for the similar segmentation of extinction based learning in cue exposure models of drug addiction. In this application, we propose to study DCS enhancement for cue exposure as applied as a relapse prevention strategy for smoking cessation. Specifically, we propose to assess the effects of two sessions of single dose DCS combined with cue-exposure treatment (CET) conducted one week apart in a randomized, double-blind, placebo-controlled, parallel group design trial. This treatment will be offered as a relapse-prevention strategy for smokers who are abstinent upon completing a standard open label 7-week smoking cessation treatment offered in our center. Outcomes will be acute changes in cue-reactivity and craving at a Post-Extinction Assessment conducted 2 days after the second CET session and maintenance of abstinence over a 6-week follow-up period. Accordingly, the proposed study has the potential of supporting for a novel cognitive remediation strategy to enhance the efficacy of cue exposure treatments for the maintenance of smoking cessation. PUBLIC HEALTH RELEVANCE: Based on successful trials in anxiety disorders and promising early data in addiction, the proposed R21 project aims to discover whether a potential novel strategy to prevent relapse to tobacco smoking is effective, and, in so doing, would advance in our understanding of neurobiological mechanisms of addiction and relapse.